CN107496181B

CN107496181B - Solubilization system containing resveratrol

Info

Publication number: CN107496181B
Application number: CN201710984065.8A
Authority: CN
Inventors: 潘树标; 张婧怡; 王峥; 王楚涵; 冯春波
Original assignee: Shanghai Jahwa United Co Ltd
Current assignee: Shanghai Jahwa United Co Ltd
Priority date: 2017-10-20
Filing date: 2017-10-20
Publication date: 2021-03-09
Anticipated expiration: 2037-10-20
Also published as: CN107496181A

Abstract

The invention relates to a solubilization system containing resveratrol, which contains resveratrol, a solubilizer containing an oxyethylene chain segment and a cosolvent containing a polyethylene glycol structure. The invention also relates to a composition containing resveratrol and a method for manufacturing the composition. The invention also relates to a method for improving the light stability of resveratrol.

Description

Solubilization system containing resveratrol

Technical Field

The present invention relates to a solubilization system containing resveratrol in which resveratrol can be stably dissolved without precipitation. The invention also relates to a method for preparing the solubilization system and a method for improving the light stability of resveratrol.

Background

Melanin is a pigment that is visible anywhere in the natural world, and has a function of blocking ultraviolet rays of a predetermined amount or more. However, if melanin pigment is excessive, the beauty may be affected, and pigmented skin diseases such as skin blackening, spots, freckles, etc. may be caused. It is known that tyrosinase acts in the process of pigmentation of the skin, and excess melanin aggregates are produced through a series of oxidation processes and accumulated in the skin. Tyrosinase is an intermediate substance that converts tyrosine into a polymer that produces melanin, and can regulate the production of melanin by inhibiting the production of tyrosinase or inhibiting the activity of the corresponding enzyme. Therefore, studies on the inhibition of the production of tyrosinase related to melanin production or the production of tyrosinase as an active substance for the purpose of cosmetic or dermatological treatment are being conducted in the art.

In the cosmetic field, particularly in the cosmetic market of asia, there is a large market for cosmetics for preventing or improving melanin deposition caused by sunlight irradiation, inflammation, pregnancy, etc., and lightening or whitening the skin. Existing products with skin whitening activity often contain ascorbyl glucoside, arbutin, plant extracts, kojic acid, vitamin C derivatives, etc., but these products often have drawbacks such as difficulty in formulation, limited penetration ability, and poor efficacy and/or safety issues. In addition, since consumers increasingly attach importance to the safety of cosmetics and wish to avoid toxicity existing in active ingredients, there is a strong demand in the market for selecting safe and effective active ingredients from natural extracts without serious side effects.

Resveratrol (3, 4', 5-trihydroxystilbene), also known as resveratrol, is a natural plant extract, is present in 72 plants of at least 21 families and 31 genera, such as red grapes, peanuts, mulberries, polygonum cuspidatum, asteraceae plants (knotted), raspberry, blueberries, and the like, and is a polyphenol compound. In recent years, more and more scientific research has shown the multifunctional benefits of resveratrol. Resveratrol is found to be an extremely potent antioxidant, regulator of genetic expression via signaling, inhibitor of inflammatory mediators, and anti-aging substance, and is capable of reducing melanin synthesis. Resveratrol can therefore be used in cosmetic compositions as a unique active ingredient in personal care products.

Although resveratrol has the above-mentioned biological activity and excellent skin whitening effect, it is difficult to formulate it into a cosmetic composition. The compound is difficult to dissolve in water (the solubility of the compound in water is about 0.03g/Kg (namely 0.003 percent) at 25 ℃), is easy to react with other chemical substances, is unstable to light, and can only be stabilized for several days even under the condition of keeping out of the sun in a high-purity resveratrol ethanol solution in a Microherb stability test. Therefore, when it is used in cosmetics, it is difficult to stably maintain it in the shelf life.

In addition, resveratrol is also unstable in cosmetic compositions in the form of O/W or W/O emulsions, it causes phase separation in the emulsion and changes the apparent color from white to yellowish brown. Thus, it has not been possible to make resveratrol be present in cosmetics at high levels so far. Furthermore, resveratrol has a tendency to precipitate (crystallize) in aqueous cosmetic compositions.

US2002/0173472 discloses a process for the preparation of a pharmaceutical formulation of resveratrol which comprises mixing an oil phase containing 5% polyethylene glycol and ethylene glycol palmitate stearate with an aqueous phase containing 0.3% xanthan gum and 48% water, based on the total weight of the formulation, and subsequently adding a mixture containing 10% resveratrol and 15% diethylene glycol monoethyl ether to form a pharmaceutical formulation (cream). Or mixing 10% resveratrol, 47.4% diethylene glycol monoethyl ether and 0.3% water to form a pharmaceutical preparation (microemulsion). This method requires the use of diethylene glycol monoethyl ether as an organic solvent in an amount of up to 15-48%, and thus cosmetics having a high organic solvent content may cause skin irritation, erythema, dryness, peeling, etc. when applied to damaged or sensitive skin, thus causing problems. In addition, high organic solvent levels are known to impair tactile comfort.

In order to solve the problems, a plurality of methods such as liposome coating, cyclodextrin coating and the like are tried in the prior art, but the technology has higher requirements on experimental equipment and components and is difficult to popularize. Therefore, there is an urgent need for an emulsion system that overcomes the disadvantages of the prior art, allowing resveratrol to be stably present in cosmetics at higher levels. In addition, the organic solvent content of the emulsion system should be low to eliminate the adverse factors that organic solvents may cause.

CN 103826597B discloses that resveratrol can be placed in a liquid crystal gel network formed by a phosphate solubilizer (such as trilaurin polyether-4 phosphate) and a solid co-emulsifier, allowing the formation of organic solvent free cosmetic emulsions. Topical compositions formed with resveratrol placed in a liquid crystal gel network exhibit good sensory properties as well as long term storage stability. However, the main disadvantage of the process of this document is that it cannot be used in transparent formulations. The common product forms of the daily cosmetics are known to be a non-transparent form and a transparent form, and the method of the patent literature can only generate milky emulsion, so the method is not suitable for being configured to form a transparent system and limits the application range of the method.

Therefore, there is a need in the art to develop a resveratrol solubilization system that can increase the solubility of resveratrol while allowing for stable storage.

There is also a need in the art to provide methods for the preparation of such resveratrol solubilization systems.

Disclosure of Invention

The invention aims to provide a resveratrol solubilization system which can increase the solubility of resveratrol and ensure that the resveratrol is stably stored.

The invention also aims to provide a preparation method of the resveratrol solubilization system.

Accordingly, one aspect of the present invention relates to a solubilization system for resveratrol comprising polyethylene glycol and/or a capped polyethylene glycol co-solvent, resveratrol and a solubilizer containing ethylene oxide segments; the weight ratio of the solubilizer to the cosolvent is 1: 6-6: 1, and the resveratrol accounts for 0.1-10 wt% of the total weight of the solubilization system.

Another aspect of the invention relates to a composition comprising resveratrol which includes a solubilization system for the resveratrol.

Yet another aspect of the present invention relates to a method for manufacturing the solubilization system, comprising mixing polyethylene glycol and/or a capped polyethylene glycol co-solvent, resveratrol and a solubilizer containing an ethylene oxide segment in a weight ratio of the solubilizer to the co-solvent of 1: 6 to 6: 1, the resveratrol being in an amount of 0.1 to 10 wt% based on the total weight of the solubilization system.

Drawings

The invention is further described below with reference to the accompanying drawings. In the attached drawings

FIG. 1 is a graph of resveratrol concentration as a function of storage conditions as determined by HPLC;

FIG. 2 is a photograph of the color status before and after the stability test of the sample;

fig. 3 is a photograph of the sample before and after being placed in an ultraviolet lamp box for 24 hours.

Detailed Description

In the present invention, the term "PEG" or "PEG structure" refers to oxyethylene or-O-CH₂-CH₂-a structure.

In the present invention, the term "capped polyethylene glycol" means a polyethylene glycol capped with C₁-C₆Alkanes, preferably C₁-C₄Alkane or C₁-C₄Carboxylic acids, preferably C₁-C₂Ethers or esters formed by reacting carboxylic acids with one or both terminal hydrogen atoms of polyethylene glycol. For example, the capped diethylene glycol may be diethylene glycol dimethyl ether, diethylene glycol monomethyl ether acetate, and the like.

In the present invention, the term "solubilizer containing an ethylene oxide segment" means a solubilizer containing an ethylene oxide segment in its structure (e.g., tween or polyoxyethylene sorbitan fatty acid ester) or a solubilizer obtained by modifying a compound by linking an ethylene oxide segment thereto. For example, hydrogenated castor oil is a common thickening, hardening or release agent, and hydrogenated castor oil having polyoxyethylene segments attached thereto to form oxyethylene segments (e.g., PEG-40 hydrogenated castor oil or PEG-60 hydrogenated castor oil) can be used as a solubilizing agent for use in the present invention.

The term "solubilizer for an oxyethylene block" of the present invention does not include polyethylene glycols of various degrees of polymerization and capped polyethylene glycols.

The inventor of the invention finds that a system formed by the cosolvent containing the PEG (polyethylene glycol) structure and the solubilizer containing the PEG structure can stably and effectively dissolve the resveratrol. Using this particular type of combination of co-solvent and solubilizer, optionally in the presence of a photo-protecting agent, can greatly enhance the solubility of resveratrol without precipitation after long-term storage, while the system has excellent photostability and is easy to apply in practice. The present invention has been completed based on this finding.

1. Resveratrol solubilization system

The resveratrol solubilization system comprises the following components:

(A) resveratrol

In the solubilization system of the present invention, resveratrol is present as an active ingredient. In one embodiment of the invention, the resveratrol is present in an amount of 0.1 to 10 wt% based on the total weight of the solubilizing system. In a preferred embodiment of the invention, the resveratrol is present in an amount of 0.5 to 9 wt%, preferably 1 to 7 wt%, more preferably 1.5 to 6 wt%, preferably 1.75 to 5 wt%, preferably 2 to 4 wt%, based on the total weight of the solubilising system.

(B) Cosolvent

The solubilization system of the present invention uses a cosolvent to treat resveratrol. From the viewpoint of improving solubility to resveratrol, the cosolvent is a polyethylene glycol solvent and/or a capped polyethylene glycol.

The degree of polymerization of the polyethylene glycol and/or capped polyethylene glycol co-solvent is not particularly limited, so long as it does not affect the solubility of resveratrol. In one embodiment of the invention, the polyethylene glycol and/or the capped polyethylene glycol has a degree of polymerization n of 2 to 18, preferably 3 to 16, more preferably 4 to 15, preferably 5 to 12, preferably 6 to 10.

The amount of the cosolvent used is not particularly limited as long as it can increase the solubility of resveratrol.

In one embodiment of the invention, the co-solvent and/or capped co-solvent is selected from the group consisting of PEG-4, PEG-6, PEG-8, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether acetate, triethylene glycol monoethyl ether, triethylene glycol dimethyl ether, triethylene glycol monoethyl ether acetate, triethylene glycol monoethyl ether formate, triethylene glycol diethyl ether, and mixtures of two or more thereof in any ratio.

(C) Solubilizer

In the solubilizing system of the present invention, a solubilizing agent is used in addition to the cosolvent. Applicants have found that not only can the solubility of resveratrol be increased, but the stability of the resulting solution can also be improved if a solubilizing agent comprising polyoxyethylene segments is combined with a preceding polyethylene glycol and/or capped polyethylene glycol co-solvent.

In the present invention, the polyoxyethylene segment-containing solubilizer excludes the polyethylene glycol and/or the capped polyethylene glycol.

The solubilizing agent suitable for use in the present invention is not particularly limited, and may be a solubilizing agent conventional in the art as long as it contains an oxyethylene segment.

In one embodiment of the present invention, the solubilizer containing polyoxyethylene segment is selected from tween (e.g., tween-20, tween-40), PPG-4-ceteth-20, beheneth-20, polyoxyethylene-modified hydrogenated castor oil (e.g., PEG-20 hydrogenated castor oil, PEG-40 hydrogenated castor oil) or a mixture of two or more thereof.

In one embodiment of the present invention, the solubilizing agent to cosolvent weight ratio in the solubilizing system is 1: 6 to 6: 1, preferably 1: 5 to 5: 1, more preferably 2: 9 to 2: 1, and particularly preferably 1: 4 to 5: 3.

(D) Hesperidin protectant

In order to improve the light stability of the final resveratrol-containing system, the solubilizing system of the invention can be optionally added with a hesperidin protective agent. The hesperidin protectant suitable for use in the solubilizing system of the present invention is selected from the group consisting of hesperidin, C, of the formula₁-C₆Alkyl hesperidin, glucosyl hesperidin or a mixture of two or more thereof.

In one embodiment of the invention, the hesperidin protectant is added in an amount of 5 to 50 wt.%, preferably 10 to 45 wt.%, more preferably 15 to 35 wt.%, and particularly preferably 20 to 30 wt.%, relative to the total amount of the solubilizing system.

2. Composition containing resveratrol

The invention also relates to a composition containing resveratrol. In one embodiment of the invention, the composition of resveratrol comprises the above-described solubilizing system of the invention and water. In another embodiment of the invention, the composition comprises 0.1 to 10 wt.% of the solubilizing system and 90 to 99.9 wt.% of water

In addition to the above components, the resveratrol-containing compositions of the invention may also include various adjuvants and additives, suitable adjuvants and additives including, for example, preservatives/antioxidants, organic solvents, silicones, thickeners, softeners, emulsifiers, opacifiers, foaming agents, antifoaming agents, humectants, fragrances, fillers, sequestering agents, anionic, cationic or amphoteric surfactants, propellants, acidifying/basifying agents, colorants (e.g., pigments, dyes), abrasives, adsorbents, astringents, pigments, skin sensates, other active ingredients, animal/plant extracts, vitamins, trace elements or any other ingredient typically formulated in skin external preparations.

The resveratrol-containing composition of the present invention is generally used as a skin external preparation, and is preferably used as a cosmetic composition, for example, as a cream, lotion, gel, lotion, essence, mask, eye cream, aerosol (cleansing foam), spray, body wash, face wash, cream, etc. In the composition containing the resveratrol, the weight percentage of the resveratrol solubilization system in the skin external preparation is 0.1-10%, preferably 0.5-9%. More preferably 1% to 5%, preferably 2% to 3%.

ADVANTAGEOUS EFFECTS OF INVENTION

The solubilization system can efficiently dissolve resveratrol, precipitation does not occur after long-time storage, and meanwhile, the stability is excellent at different temperatures and the application is easy.

The method of the invention can ensure that the resveratrol exists stably under illumination, particularly under ultraviolet rays, and does not change color.

The resveratrol-containing solubilization system can conveniently form various products containing resveratrol by adding water and various additives and/or auxiliary agents. The resveratrol in the system can be kept stable and can not be precipitated after long-term storage.

Examples

The present invention is further illustrated by the following examples, but is not limited thereto.

Examples 1 to 5 and comparative examples 1 to 9：

According to the formulation shown in Table 1, the solubilizer was accurately weighed, added to the cosolvent, heated to 40-50 deg.C, and uniformly dispersed with stirring. Adding resveratrol into the mixture of solubilizer and cosolvent, heating to 60 deg.C, and stirring. At room temperature, deionized water is slowly added into the solution, and the solution is slowly stirred until the system is completely uniform.

Example 6：

The samples of examples 1 to 5 and comparative examples 1 to 9 were allowed to stand at room temperature in the dark for one week, and whether or not the sample precipitated before and after the standing was observed, and the data are summarized as follows (good means no precipitation, and good means unstable precipitation).

TABLE 1

As can be seen from the data of examples 1 to 5 and comparative examples 1 to 3, the solubilizers contained in examples 1 to 5 all comprise polyoxyethylene chain segments, so that the resveratrol can be well dissolved, and the stability of the resveratrol in the formula is improved, so that the resveratrol is not precipitated. In comparative examples 1 to 3, however, the solubilizer structure contained no polyoxyethylene segment, and resveratrol was unstable in the sample and could be directly precipitated.

From the data of example 5 and comparative examples 4 to 9, it is seen that in comparative example 4 in which no cosolvent is used, a simple solubilizer can achieve the effect of solubilization in a short time, but precipitates again after standing. A plurality of commonly used cosolvents are tried in experiments, but the solubilization effect on resveratrol is not realized, the precipitation of resveratrol is accelerated, and the resveratrol is precipitated immediately after the sample preparation is completed. Only by using PEG-8 as a cosolvent, resveratrol can be effectively solubilized, the stability is improved, and no precipitation phenomenon occurs even when a sample is kept still for one week.

For long-term stability observation of the sample of example 5, the sample was left standing for 1 month at room temperature, 4 ℃, 40 ℃ and 48 ℃ under dark conditions, respectively, and the change in the concentration of resveratrol in the sample was detected by HPLC and the color change of the sample was judged with the naked eye.

The results are shown in FIGS. 1 and 2. FIG. 1 is a graph showing the change in resveratrol concentration in samples of example 5 as determined by HPLC under different storage conditions of stability in example 6. FIG. 2 is a photograph of the color state of the sample of example 5 after stability examination in example 6. The results show that the resveratrol content did not change significantly after storage at different temperatures, indicating that the composition has good stability at different temperatures. And the color of the sample is not changed, which also indicates that the color stability of the sample is good.

Example 7 and comparative examples 10 to 12：

According to the formulation shown in Table 2, the solubilizer was accurately weighed, added to the cosolvent, heated to 40-50 deg.C, and uniformly dispersed with stirring. Adding resveratrol into the mixture of solubilizer and cosolvent, heating to 60 deg.C, and stirring. At room temperature, deionized water is slowly added into the solution, and the solution is slowly stirred until the system is completely uniform.

TABLE 2

Example 8：

The products of examples 5 and 7 and comparative examples 10 to 12 were placed in an ultraviolet lamp cabinet for 24 hours. The content change of resveratrol before and after ultraviolet irradiation of the sample was measured by HPLC.

TABLE 3

As can be seen from the data of example 5 in table 3, the solubilization system of resveratrol without protective agent is very unstable under uv light, and only about 40% of resveratrol remains after 24 hours of uv irradiation.

The changes of L, a, and b in the L a b color system of the sample before and after the ultraviolet irradiation for 24 hours were measured using a color difference meter, and differences Δ L, Δ a, and Δ b between the sample before and after the irradiation were obtained.

TABLE 4

Furthermore, as can be seen from the data in Table 4 of example 5, UV light causes the color of the resveratrol-containing sample to turn yellow. Reference is also made to fig. 3. FIG. 3 is a photograph of the samples of examples 5 and 18 and comparative examples 10 to 12 before and after being placed in an ultraviolet light box for 24 hours, and it can be seen from the photograph that resveratrol is very unstable under ultraviolet light, and the color of the resveratrol-containing sample turns yellow after being irradiated by ultraviolet light for 24 hours. From left to right are

Examples 5 and 7, and comparative examples 10 to 12.

From the data of example 7 in tables 3 and 4, it is clear that the stability of resveratrol under ultraviolet rays can be maintained after the addition of glucosyl hesperidin, and the color of the sample is not changed before and after the light irradiation. In comparative examples 10 and 11, in which other protective agents (niacinamide, ascorbic acid) were added, resveratrol could not be protected under ultraviolet rays, and resveratrol degradation close to 60% was still observed. In comparative example 12 in which a sunscreen agent (a combination of disodium phenyldibenzoimidazole tetrasulfonate and arginine) was added, resveratrol was stable under ultraviolet rays, and 90% of resveratrol remained, but the sunscreen agent did not prevent the color change of the sample from the appearance color, and thus it was not preferable.

Examples 9 to 14：

Accurately weighing solubilizer according to the formula shown in Table 5, adding the solubilizer into cosolvent, heating to 40-50 deg.C, stirring and dispersing uniformly for use; adding resveratrol into the mixture of the solubilizer and the cosolvent, heating to 60 ℃, and uniformly stirring for later use; at room temperature, deionized water is slowly added into the solution, and the solution is slowly stirred until the system is completely uniform.

Example 15：

The products of examples 9 to 14 were allowed to stand at room temperature in the dark for one week, and the samples before and after standing were observed for precipitation, and the data are summarized as follows (good quality means no precipitation, and good x means unstable precipitation).

TABLE 5

As can be seen from the data in Table 5, the PEG structure solubilizers with different concentrations and the PEG cosolvent with different concentrations have the solubilizing effect on resveratrol, and the stability is very good.

Comparative example 13 and examples 16 to 19：

Accurately weighing solubilizer according to the formula shown in Table 6, adding the solubilizer into cosolvent, heating to 40-50 deg.C, stirring and dispersing uniformly for use; adding resveratrol into the mixture of the solubilizer and the cosolvent, heating to 60 ℃, and uniformly stirring for later use; at room temperature, deionized water is slowly added into the solution, and the solution is slowly stirred until the system is completely uniform.

Example 20:

the samples of examples 5, 16 to 20 and comparative example 13 were left to stand at room temperature for one week in the dark, and the state of the sample was observed to see whether or not any precipitate was precipitated, and the data are summarized as follows (o indicates no precipitate was formed uniformly, and X indicates that the precipitate was not stable)

TABLE 6

As can be seen from the above examples and comparative examples, if the PEG chain contained in the solubilizer is too short, solubilization of resveratrol cannot be achieved, and when the PEG chain contained in the solubilizer is longer than a certain length, for example, the degree of polymerization of PEG is 20 or more, solubilization of resveratrol can be achieved.

The resveratrol compositions prepared in examples 1 to 15 were used for preparing skin external preparations, and application examples 1 to 11 were obtained. The following shows the formulations, formulations and preparation methods of application examples 1 to 11 in which the resveratrol composition is applied to a skin external preparation.

Application example 1: preparation of face cream

Application example 31: preparation of the emulsion

Application example 32: preparation of jelly

Application example 33: preparation of astringent

Application example 34: preparation of essence

Application example 35: preparation of facial mask

Application example 36: preparation of eye cream

Application example 37: preparation of an aerosol (cleaning foam)

Application example 38: preparation of the spray

Application example 39: preparation of shower gel

Application example 40: preparation of facial cleanser

Claims

1. A resveratrol solubilization system comprises resveratrol, solubilizer containing oxygen-containing ethylene chain segment, polyethylene glycol as cosolvent and/or capped polyethylene glycol; the weight ratio of the solubilizer to the cosolvent is 1: 4 to 1.66: 1, the resveratrol accounts for 0.1-2 wt% of the total weight of a solubilization system, the solubilizer containing the oxygen ethylene chain segment is selected from polysorbate-20, PPG-4-cetyl polyether-20, behenyl polyether-20 and polyoxyethylene modified hydrogenated castor oil, and the cosolvent is PEG-8.

2. The resveratrol solubilization system according to claim 1, wherein the degree of polymerization of the oxyethylene block in the ethylene block-containing solubilizer is in the range of 20 to 80.

3. The resveratrol solubilization system according to claim 1 or 2, further comprising a hesperidin protectant.

4. Chenopodium album linn as claimed in claim 3The resveratrol solubilization system is characterized in that the hesperidin protectant is selected from hesperidin and C₁-C₆Alkyl hesperidin, glucosyl hesperidin or a mixture of two or more thereof.

5. A resveratrol solubilization system according to claim 4, wherein the hesperidin protectant is present in an amount of 5-50 wt% based on the total amount of the solubilization system.

6. A resveratrol-containing composition comprising 0.1-10 wt% of the resveratrol solubilization system according to any of claims 1-5 and 90-99.9% of water.